Ethinyl and vinyl derivatives of 19-norandrostan-3beta, 17beta-diol



United States Patent 3,084,173 ETHINYL VlNYL DERIVATIVES 0F 19-NOR=ANDROSTAN-3BJ7 3-DIOL Howard J. Ringold, Albert Bowers, and GeorgeRosenkranz, all of Mexico City, Mexico, assignors, by mesne fssignments, to Syntex Corporation, a corporation of anama No Drawing.Filed Apr. 10, 1958, Ser. No. 727,522 Claims priority, applicationMexico Apr. 11, 1957 5 Claims. (Cl. 260-397.4)

The present invention relates to novel cyclopentanophenanthrenederivatives and to a process for the production thereof.

More particularly the present invention relates to the novel19-nor-androstan-3fi,l'lB-diol and C-l7 lower alkyl, ethinyl and vinylderivatives thereof as well as the corresponding esters, to a novelprocess for the production of these compounds and to certain novelintermediates. The novel final products of the present invention i.e.19-norandrostan-3,8,175-diol, the 17oc-10W1' alkyl derivatives,17oc-Vll1Yl derivatives, l7a-ethinyl derivatives and the esters of thesecompounds are all hormones of the androgenic type having a relativelyhigh anabolic-androgenic ratio as well as a pronounced anti-estrogenicefiect. They are therefore valuable for the shrinkage of mammary glands,for the building of dihabilitated tissue and for other well knownanti-estrogenic and anabolic efiects,

since they also produce a minimum of androgenic action.

In US. Patent No. 2,756,244, granted July 24, 1956, there is disclosedand claimed the androgenic type hormone 19-nor-androstan-17fl-ol-3-onewhich as pointed out in this patent possesses a favorableanabolic-androgenic ratio. In accordance with the present invention ithas been discovered that treatment of this compound with an alkali metaldouble hydride reducing agent such as lithium aluminum hydride or sodiumborohydride reduces the 3- keto group to a 3(3-hydroxy group to give thenovel 19- nor-androstan-3/3,17,3-diol which possesses a much morefavorable anabolic-androgenic ratio than the starting 3- ketone. Furtherthe diol is a much more desirable anti estrogenic agent and possesses alesser androgenic effect than the 3-ketone. It has further beendiscovered in accordance with the present invention that 17a-loweralkyl, 17a-vinyl and 17a-ethinyl derivatives of 19-nortestosterone ontreatment with an alkali metal such as lithium in liquid ammonia givethe corresponding intermediate androstane derivatives and theseandrostane derivatives on reduction with the hydride reducing agentshereinbefore mentioned give the corresponding novel 17alower alkyl,l7avinyl and l7a-ethinyl-androstan-3B,17B- diols. These Hot-substituteddiols are also valuable androgenic type hormones of highly favorableanabolicandrogenic ratio and desirable anti-estrogenic agents. The samevalue properties are also exhibited by the esters ofandrostan-3fi,17B-diol and its l7a-lower alkyl, 17ccvinyl, 17u-ethinylderivatives hereinafter set forth in detail. Further the novelintermediate 17u-vinyl-androstanl7fi-ol-3-one is also an androgenic typehormone having a high anabolic-androgenic ratio and antiestrogenicvalue.

The novel compounds of the present invention may therefore beillustrated by the following formulas:

OH In" In the above formula R represents hydrogen or an acyl group ofthe type conventionally known in the steroid art. These acyl groups arethose derived from hydrocarbon carboxylic acids having up to 12 carbonatoms such as acetate, propionate, benzoate, caproate, undecenoate, andcyclopentylpropionate. R represents hydrogen, a lower alkyl group ofless than 7 carbon atoms such as methyl, ethyl or propyl, vinyl orethinyl. R is the same as R- when R is hydrogen and R representshydrogen when R is lower alkyl, vinyl or ethinyl.

The novel compounds set forth above are produced by a processillustrated by the followingequation:

alkali metal O: ammonia 0:

n od In the above equation R, R and R represent the same groups asheretofore set forth. 7

In practicing the invention above outlined 19-nortestosterone or its17-alkyl, vinyl or ethinyl derivative in an inert organic solvent suchas dioxane or ether or a mixture of dioxane and ether is added to asolution of an alkali metal such as lithium in liquid ammonia. After thehydrogenation is completed the ammonia is allowed to evaporate and theproduct conventionally purified to give the corresponding saturated allo(androstane) derivative. For the second step above outlined theandrostane compound is dissolved in an inert organic solvent and treatedat room temperature with a hydride reducing agent such as sodiumborohydride or lithium aluminum hydride and then conventionallypurified.

Treatment of 19-nor-androstan-3fi,17;8-diol thus produced withconventional esterifying agents such as an acid anhydride or chloride ofa hydrocarbon carboxylic acid of up to 12 carbon atoms in pyridine forexample gave the corresponding 3,17-diacylates. As may be understoodthese acylates may be derived from acids which may be saturated orunsaturated, straight or branched chain, cyclic or cyclicaliphaticandmay be substituted as known in the art with for example halogen groups.The same conventional esterification of the 17ot-alkyl, vinyl or ethinylcompounds gave the 3-mono-acylates.

The following specific examples serve to illustrate but are not intendedto limit the present invention.

reducing agent Example I A solution of 15 g. of17a-ethinyl-l9-nor-testosterone in a mixture of cc. of dioxane and 120cc. of ether was rapidly added to a mechanically stirred solution of2.25 g. of lithium in 1500 cc. of liquid ammonia. 30 g. of ammoniumchloride was added, the ammonia was allowed to evaporate, water wasadded to the residue and the product was extracted with methylenedichloride. The extract was washed with water, dried over sodium sulfateand evaporated to dryness. The residue was chro- 3 matographed on washedalumina, thus yielding 17aethinyl-19-nor-androstan-17fl-ol-3-one, M.P.222-223" C., [1x1 +6 (chloroform).

Similarly, 19-nor-testosterone was converted into 19-nor-androstan-17fl-ol-3-one; Hot-vinyl-19-nor-testosterone afforded17a-vinyl-19-nor-androstan-175-ol-3-one (M.P. 192-193 C., [01] +47(chloroforrn)), 17u-ethy1-19- nor-testosterone produced17a-ethyl-19-nor-androstan-17B- ol-3-one (M.P. 212-214 C., [:1 +33(chloroform)) and 17a-methyl-l9-nor-testosterone gave 17a-n1ethyl-19-nor-androstan-17B-ol-3-one.

470 mg. of 17-ethinyl-l9-nor-androstan-175-o1-3-one was dissolved in 30cc. of dioxane and treated with 300 mg. of sodium borohydride dissolvedin 5 cc. of dioxane and the mixture was kept for 1 hour at roomtemperature. It was then acidified with acetic acid, diluted with waterand extracted with chloroform. The extract was washed with 'water, driedover anhydrous sodium sulfate and evaporated to dryness. Crystallizationfrom acetone produced the pure17u-ethinyl-19-nor-androstane-3/3,17,8-diol, M.P. 192-193 C., [oz] 42(chloroform).

Similarly, 19-nor-androstan-17fl-ol-3-one was converted intol9-nor-androstane-313,175-diol (M.P. 168-170 C., [11],; +17(chloroform)); 17u-vinyl-19-nor-androstan- 17B-ol-3-one afforded17u-vinyl-19-nor-androstane-35, 17fl-diol (M.P. 167-169 C., [ab +9(chloroform)); 17a-ethyl-19-nor-androstan-17B-o1-3-one produced17aethyl-l9-nor-androstane-3B,17B-diol (M.P. 181-183 C., [1:] +2(chloroforn1)); and 17m-methyl-19-nor-androstan-17fl-oi-3-one gaveNot-methyl-19-nor-androstan- 35,17,6-diol.

Example 11 A mixture of l g. of 17a-ethyl-19-nor-androstane-3p,17B-diol,20 cc. of pyridine and 1 cc. of acetic anhydride was allowedto react at room temperature for 12 hours and then poured into Water.The mixture was heated for half an hour and cooled. The precipitate wascollected and recrystallized several times from acetone, thus yieldingthe 3-acetate of 17x-ethyl-19-nor-androstane- 3p,17fi-diol. I

By similar conventional esterification using the corresponding acidanhydride or halide there was produced the 3-propionate, butyrate,hemisuccinate, caproate, trimethylacetate, cyclopentylpropionate,benzoate, phenoxypropionate and fi-chloropropionate.

The same esters were also prepared of the 17a-vinyl, ethinyl and methylderivatives of Example I.

Reaction in a similar way give the corresponding 3,17- diesters ofl9nor-androstan-3fi,l7fl-diol.

We claim:

-1. 17u-vinyl-19-nor-androstan-3/3,17,8-dio1.

2. The hydrocarbon carboxylic acid 3-monoesters of17a-vinyl-l9-nor-androstan-3fi,17fi-diol.

4. The hydrocarbon carboxylic acid 3-monoesters ofl7a-ethinyl-19-nor-androstan-318,17,8-diol.

5. 17u-vinyl-19-nor-androstan-1718-01-3-one.

References Cited in the file of this patent UNITED STATES PATENTS2,094,045 Schoeller et al. Sept. 28, 1937 2,662,089 Murray et al. Dec.8, 1953 2,756,244 Djerassi et al. July 24, 1956 2,842,570 Herr July 8,1958 2,861,087 Herr Nov. 18, 1958 2,881,191 Herr Apr. 7, 1959 OTHERREFERENCES Fukushimia et al.: J. A. C. 8., vol. 73, pages 196-201(1951).

Patel et al.: J. Che-m. Soc. (1952), pages 161.5.

Brooks et al.: Bio. Chem. J., vol. 54, pages 212-7 (1953).

Rapala et al.: J. Org. Chem., vol. 23, pages 1404-5 (1958).

1. 17A-VINYL-19-NOR-ANDROSTAN-3B,17B-DIOL.